Novel 5, 6-dihydro-11h-pyrido[2, 3-b][1, 5]benzodiazepines



United States Patent 3,326,900 NOVEL 5,6-DIHYDRO-l1H-PYRIDO[2,3-b][1,5] BENZODIAZEPINES Giinther Schmidt, Biberach an der Riss, Germany, as-

signor to Boehringer Ingelheim G.m.b.H., Ingelheim am Rhine, Germany, a corporation of Germany No Drawing. Filed Feb. 23, 1965, Ser. No. 434,666 Claims priority, applici ltion ggrmany, Feb. 28, 1964,

7 Claims. ((313260-2393) This invention relates to novel 5,6-dihydro-1 lH-pyrido- [-2,3-b] [1,'5]benzodiazepines and acid addition salts thereof, as well as to various methods of preparing these compounds.

More particularly, the present invention relates to 5,6- dihydro -1'1H pyrido[=2,3-b] ['l,5]benzodiazepines of the where X and Y are lower alkyl or, together with each other and the nitrogen atom to which they are attached, form a basic saturated heterocyclic ring, and

R" is hydrogen or lower alkyl;

R and R, which may be identical to or different from each other, are hydrogen, halogen, lower alkyl, lower alkoxy, trifiuoromethyl, carboxyl or carbalkoxy, and

Z is carbonyl or methylene,

and their non-toxic, pharmacologically acceptable acid addition salts. The compounds according to the present invention may be prepared by various methods, among which the follow-. ing have proved to be most convenient and eflicieut:

Method A By converting a 5-oxo-5,6-dihydro 1'1H-pyrido[2,3 b] [1,5 Jbenzodiazepine of the formula wherein R and R" have the same meanings as in Formula I, into the corresponding 6-alkali metal compound, reacting the alkali metal compound with a compound of the formula wherein R has the same meanings as in Formula I and X is the radical of a reactive ester, such as a halogen atom or the radical of a sulfuric acid ester or an aromatic 3,326,900 Patented June 20, 1967 QR Ill H (IV) wherein R, R and R" have the same meanings as in Formula I, and subsequently reducing compound 1V to obtain a compound of the Formula I wherein Z is methylene.

The conversion of compound II into the corresponding alkali metal compound may be eifected by reacting compound with an alkali metal hydroxide, an alkali metal alcoholate, an alkali metal amide or an alkali metal hydride. The reaction is preferably carried out at elevated temperatures and in the presence of an inert organic solvent; if an alkali metal hydroxide is used, an aqueous organic solvent may also be employed.

For conversion of the alkali metal-substituted S-oxo- 5,6 dihydro-11H-pyrido[2,3-b] [l,5]benz-odiazepine thus obtained into compound IV, the solution or suspension of the alkali metal compound is reacted directly, i.e., without isolation of the reaction product, with compound III at elevated temperatures, preferably at the boiling point of the solvent or suspension medium or at the boiling point of compound III, whichever is lower. The substitution surprisingly takes place exclusively on the nitrogen atom in the 6-position of the pyridobenzodiazepine. The substitution product IV may, if desired, be purified through an acid addition salt thereof, which may be formed by conventional methods.

The reduction of compound 1V is effected preferably with the aid of lithium aluminum hydride in an inert anhydrous solvent at moderately elevated temperatures, advantageously at the boiling point of the particular solvent used. Examples of anhydrous solvents suitable for this purpose are ether, tetrahydrofuran and dioxane. In the event that compound 1V is poorly soluble in the anhydrous solvent, it may be gradually extracted into the reaction vessel from a conventional extraction apparatus.

The reduction of compound 1V may, however, also be carried out by other conventional methods, for instance, with hydrogen in the presence of a hydrogenation catalyst, preferably in the presence of a copper-chromium oxide catalyst in an inert organic solvent, such as di'oxane, at temperatures between and 250 C. and at a pressure between 100 and 250 atmospheres gauge. The reduction may further be efl'ected by means of an alkali metal in an absolute lower alkanol pursuant to Bonveault- Blanc, Compt. rend, 136, 1:676 (1903) Method B By reducing a compound of the Formula II to form 5,6-dihydro-1lH-pyrido[2,3-b] [l,5]benzodiazepine of the wherein R and R" have the same meanings as in Formula I, and reacting compound V with a compound of the Formula III. This method yields compounds of the Formula I wherein Z is methylene.

The reduction of compound II may be accomplished by any of the methods described for the reduction of compound IV in Method A; that is, preferably with lithium aluminum hydride in an inert anhydrous solvent at moderately elevated temperatures, or also by catalytic hydrogenation or by reduction with an alkali metal in an absolute lower alkanol. The reduction product V may, if desired, be purified through an acid addition salt thereof, which may itself be prepared by conventional methods.

The reaction of compound V with compound III is preferably carried out in the presence of an organic solvent at elevated temperatures, preferably at the boiling point of the solvent. Examples of suitable organic solvents are aliphatic alcohols and aromatic hydrocarbons; however, a stoichiometric excess of compound III may also be used as a solvent medium.

' If desired, an inorganic base may be added to the reaction mixture of compounds V and III as an acid-binding agent, that is, as an agent capable of binding or neutralizing the acid HX released by the reaction, where X has the same meanings as in Formula III, in which case the reaction product is a pyridobenzodiazepine of the Formula I in which Z is methylene in the free base form. Normally, however, the reaction is performed without an acid-binding agent, whereby the acid HX released by the reaction immediately combines with the basic pyridobenzodiazepine product to for-m an acid addition salt thereof. If desired, this acid addition salt may be converted into the free base form by conventional methods, for instance, by neutralizing the acid addition salt with an inorganic base.

The i5-oxo-5,6-dihydro-1lH-pyrido[2,3-b] [1,5] benzodiazepines of the Formula II which are used as starting materials in Methods A and B are described in my copending application Ser. No. 427,503 filed Jan. 22, 1965, entitled 5,6 dihydro-S-oxo-l1H-pyrido[2,3-b] [1,5]ben zodiazepine Derivatives and Process. Compounds of the Formula I may, if desired, be converted into their non-toxic, pharmacologically acceptable acid addition salts by conventional methods; for example, by dissolving the free base compound I in a suitable solvent and acidifying the solution with one or more molar equivalents of the desired acid. Examples of inorganic and organic acids which will form non-toxic, pharmacologically acceptable addition salts with a compound of the Formula I are the following: Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, tartaric acid, citric acid, succinic acid, malic acid, methane-sulfonic acid, 8-chloro-theophylline and the like. Compounds of-the Formula I wherein R is other than a basic substituent form acid addition salts with one molar equivalent of the acid, whereas those wherein R is a basic substituent form addition salts with more than one molar equivalent of the acid.

The following examples further illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be understood, however, that the invention is not limited to the particular examples given below.

EXAMPLE 1 Preparation of 5,6-dihydro-5-oxy-6-methyl llH-pyrido [2,3-b][1,5]benzdiazepine and 5,6-dihydro-6-methylpyrido [2,3-b-1 [1,51benz0diaZepine by method A (a) 21.1 gm. (0.1 mol) of 5,6-dihydro--oxo-11H- pyrido[2,3-b] [1,5]benzodiazepine were dissolved in a warmed mixture of 300 cc. ethanol and 20 cc. aqueous 30% sodium hydroxide, and the resulting solution was admixed with 46 gm. (0.4 mol) of 'methyliodide. Thereafter, the mixture was refluxed for four hours. The reaction mixture was then evaporated in vacuo, and the residue was washed with water and recrystallized from ethanol. The product had a melting point of 171 C. and

4 was identified to be 5,6 dihydro-5-oxo-6-methyl-11H- pyrido[2,3] [1,5]benzodiazepine of the formula hydrofuran and then an aqueous potassium tartrate solution. The organic phase was separated and evaporated in vacuo. The oily residue was distilled in vacuo, and the fraction passing over between 153 and 155 C. at 0.05 mm. Hg was recrystallized from cy-clohexane. The product had a melting point of 9193 C. and was identified to be 5,6-dihydro-6-methyl-11H pyrido[2,3b][1,5]benzodiazepine of the formula 73.91%; H, 6.20%; N, 19.89%. Found: C, 74.00%; H, 6.47%; N, 20.05%.

EXAMPLE 2 Preparation of 5,6 dihydro-S-oxo-tS-ethyl 11H pyrido [2,3-b] [1,51benzodiazepine and 5,6 dihydr0-6-ethyl- 11H-pyrid0[2,3-b] [1,5]benzodiazepine by method A (a) 10.0 gm. (0.0475 mol) of 5,6-dihydro-5-oxo-11H- pyrido[2,3-b] [1,5]benzodiazepine were dissolved in a mixture consisting of 40 cc, of a potassium tert. butylate solution (from 2.14 gm. of potassium and 40 cc. of tert. butanol) and cc. of absolute dioxane, and the resulting solution Was refluxed for two hours. Thereafter, 15.6 gm. (0.1 mol) of ethyliodide Were added and the mixture was refluxed for four hours. The reaction mixture was then filtered to remove the precipitated potassium iodide, and the filtrate was evaporated in vacuo. The residue was recrystallized from ethanol, yielding a compound having a melting point of 148151 C., which was identified to be 5,6-dihydro-5-oxo-6-ethyl-11H-pyrido[2,3-b] [1,5]benzodiazepine of the formula 0 C2H5 at.

(b) 5.8 gm. of the product of step (a) were reduced 5 with 4.0 gm. of lithium aluminum hydride in 200 cc. of absolute tetrahydrofuran and the reaction mixture was worked up, as described in Example 1(b), The oily product had a boiling point of 135-139 C. at 0.05 mm. Hg. It was identified to be 5,6-dihydro-6-ethyl-1lH-pyrido [3,2-b] [l,5]benzodiazepine of the formula Analysis.-C H N mol. wt. 225.3. Calculated: C, 74.64%; H, 6.71%; N, 18.65%. Found: C, 74.75%; H, 7.00%; N, 18.60%.

EXAMPLE 3 Preparation of 5,6-dihydro 5 oxo-6-benzyl-11H-pyrz'do [2,3-b] [1,5]bemzdiazepine and 5,6-dihydr0-6-benzyl- 11H-pyrid0[2,3-b] [1,5]benzodiazepine by method A (a) 21.1 gm. (0.1 mol) of 5,6-dihydro--oxo-l1H- pyrido[2,3-b][1,5]benzodiazepine were dissolved in 250 cc. of a warmed sodium butylate solution (2.5 gm. sodium in 250 cc. butanol). Thereafter, about half of the butanol was distilled off in vacuo and then about 250 cc. of 1,2,3,4-tetrahydronaphthalene were added, and the remaining butanol was distilled ofi. To the resulting suspension of 5,6-dihydro-5-oxo-6-sodium-1lH-pyrido[2,3-b] [1,5]benzodiazepine in tetrahydronaphthalene 17.1 gm. (0.1 mol) of benzyl bromide were added, and the mixture was heated at about 200 C. for seven hours while stirring. Thereafter, the precipitated sodium. bromide was filtered oflf, and the filtrate was evaporated in vacuo. The residue was distilled (B.P. MO-245 C. at 0.06 mm. Hg) and recrystallized from ethanol. The product had a melting point of 178-180 C. and was identified to be 5,6-

dihydro 5 oxo 6 benzyl 11H pyrido[2,3-b] [1,5] benzodiazepine of the formula The yield was 74% of theory.

Analysis.C I-I N O; mol. wt. 301.3. Calculated: C, 75.73%; H, 5.02%; N, 13.95%. Found: C, 75.60%; H, 5.06%; N, 13.94%.

(b) 10.6 gm. of the product of step (a) were reduced with 4 gm. of lithium aluminum hydride in absolute tetrahydrofuran and the reaction mixture was worked up, as described in Example 1(b). The raw product had a boiling point of ISO-190 C. at 0.05 mm. Hg, and after recrystallization from cyclohexane had a melting point of 111-112 C. It was identified to be 5,6-dihydro-6-benzyl- 1lH-pyrido[2,3-b] [1,5 ]benzodiazepine of the formula GE -C5115 CH2C Analysis.C H N mol. Wt. 287.4. Calculated: C, 79.41%; H, 5.96%; N, 14.63%. Found: C, 79.25%; H, 5.97%; N, 14.70%.

6 EXAMPLE 4 Preparation of 5,6-dihydr0 5 0x0-6,8-dimethyl-1IH- pyrido[2,3-b] [1,5 Jbenzodiazepine and 5,6-dihydro-6,8- dimethyl 11H pyrid0[2,3-b] [1,5] benzodiazepine by method A (a) 22.5 gm. (0.1 mol) of a compound believed to be 5,6 dihydro 5 oxo-S-methyl-l1H-pyrido[2,3-b][1,5] benzodiazepine (the position of the methyl-substituent has not yet been established; it could also be in the 9- position) were reacted with 46 gm. of methyl iodide in a mixture consisting of 300 cc. ethanol and 20 cc. aqueous 30% sodium hydroxide, as described in Example 1(a). Recrystallized from ethanol, the product had a melting point of 208 C. It was believed to be the compound of the probable formula Analysis.-C H N O; mol. wt. 239.3. Calculated: C, 70.28%; H, 5.47%; N, 17.56%. Found: C, 70.40%; H, 5.53%; N, 17.57%.

(b) The product obtained in step (a) was reduced with lithium aluminum hydride and the reaction mixture was worked up, as described in Example 1(b). The raw reduction product had a boiling point of 155-160 C. at 0.05 mm. Hg; after recrystallization from isopropanol it had a melting point of C. It was believed to be the compound of the probable formula Analysis.-C H N mol. wt. 225.3. Calculated: C, 74.64%; H, 6.71%; N, 18.65%. Found: C, 74.65%; H, 6.85%; N, 18.55%.

EXAMPLE 5 Preparation of 5,6-dihydr0-5-ox0-6 (5 dimethylaminoethyl)-1]H-pyrido[2,3-b] [1,5]benz0diazepine, ifs hydrochloride and 5,6-dihydr0-6-(fi-dimethylaminoethyl)- 11H-pyrid0[2,3-.b] [1,5]benzodiazepine by method A 0.2 mol of fi-dimethylaminoethyl chloride was added to a suspension of 0.1 mol of the 6-sodium derivative of 5,6-dihydro-5-oxo-1 1H-pyrido[2,3 -b] 1,5] benzodiazepine in absolute xylene, which was prepared in a manner analogous to that described in Example 3(a) except that xylene was used instead of tetrahydronaphthalene. The resulting mixture was heated for four hours at about C., accompanied by stirring. Thereafter, the reaction mixture was allowed to cool, was then filtered, and the filtrate was shaken with aqueous 10% hydrochloric acid. The acid aqueous phase was separated, made alkaline with sodium hydroxide and extracted with chloroform. The chloroform extract solution was dried over sodium sulfate, evaporated in vacuo, and the residue was distilled in vacuo. The fraction passing over between and 187 C. at 0.06 mm. Hg was identified to be 5,6-dihydro- 7 5-oxo-6-(t3 dimethylamino ethyl) 11H pyrido[2,3-b] [1,5]-benzodiazepine of the formula E) (621 4- 3) 2 ON The yield was 58% of theory.

An\aZysis.C I-I N O; mol. wt. 282.3. Calculated: C, 68.06%; H, 6.43%; N, 19.84%. Found: C, 68.00%; H, 6.54% N, 20.00%.

A small sample of the product thus obtained was admixed with an equimolar amount of aqueous hydrochloric acid, the resulting solution was evaporated, and the residue was recrystallized from ethanol, yielding the hydrochloride of the free base product. It had a melting point of 240 C.

Analysis.C H ClN O; mol. wt. 318.8. Calculated: C, 60.28%; H, 6.01%; Cl, 11.12%. Found: C, 60.20%; H, 6.07%; Cl, 10.90%.

(b) The free base product obtained in step (a) was reduced with lithium aluminum hydride and the reaction mixture was worked up, as described in Example 1(b). The reduction product had a boiling point of 160-165 C. at 0.08 mm. Hg. It was identified to be 5,6-dihydro-6-(l3- dimethylarnino-ethyl)11H-pyrido[2,3-b][1,5 benzodiazepine of the formula Analysis.-C H N mol. wt. 268.4. Calculated: C, 71.61%; H, 7.51%; N, 20.88%. Found: C, 71.50%; H, 7.50%; N, 21.30%.

EXAMPLE 6 Preparation of 5,6 dihydro 5-ox0-6-(B-dimethylaminoethyl)-8(or 9) chloro-IIH-pyrido[2,3-b] [1,51-benzdtlazepine and 5,6-dihydr0-6-(B-dimethylamino-ethyl)- 8(0r 9) chloro 11H-pyrid0[2,3-b] [1,5]ben1z0di;azepine my method A 0.1 mol of the 6-sodium derivatives of 5,6-dihydro-- oxo-8(or 9) chlor-o-11H-pyrido[2,3-b][1,51benzodiazepine (the exact point of attachment of the chlorine-substituent had not been established) was reacted with 0.2 mol of B-dimethylaminoethyl chloride in absolute xylene in a manner analogous to that described in Example 5 (a). The raw product had a boiling point of 185-195 C. at 0.05 mm. Hg; recrystallized from petroleum ether, it had a melting point of 112 C. It was believed to be 5,6-dihydro-5-oxo-6- fi-dimethyl-aminoet-hyl) -8 (or 9) -chloro-1 1H- pyrido [2,3-b] [1,51benzodiazepine.

Analysis.C H ClN O; mol. wt. 316.8. Calculated: C, 60.66%; H, 5.41%; N, 17.69%. Found: C, 60.60%;

The product thus obtained was reduced with lithium aluminum hydride and the reaction mixture was worked up, as described in Example b). The reduction product had a boiling point of 169-171 C. at 0.025 mm. Hg and was believed to be 5,6-dihydro-6(B-dimethylamino-ethyD- 8 (or 9) -chloro-1 1H-pyrido[2,3-b] [1,5 benzodiazephine.

8 EmMPLE 7 Preparation of 5,6 dihyaro-6-benzyl-11H-pyrid0[2,3-b]

[1,51benz0diazepiwe by method B (a) 5.0 gm. of 5,6-dihydro-5-oxo-11H-pyrido[2,3-b] [1,5]benzodiazepine were gradually extracted over the course of four hours from a Thielepape extraction apparatus into a round-bottom flask containing a solution of 4.0 gm. of lithium aluminum hydride in 200 cc. of absolute dioxane. After completion of the extraction the reaction mixture Was refluxed for one hour, allowed to cool and then decomposed in customary fashion by adding first aqueous dioxane and then an aqueous potassium tartrate solution. The organic phase was separated and evaporated in vacuo. The oily residue was distilled in vacuo. The major fraction passing over between and C. at 0.05 mm. Hg was recrystallized from carbon-tetrachloride, yielding a compound having a melting point of 125l26 C. It was identified to be 5,6-dihydro-11H-pyrido [2,3-b] [1,5]benzodiazepine. The yield was 58% of theory.

Anlalysis.C H N mol. wt. 197.2. Calculated: C, 73.07%; H, 5.62%; N, 21.31%. Found: C, 73.00%; H, 5.78%; N, 21.43%.

(b) 0.02 mol of the end product of step (a) was refluxed for two hours with a solution of 0.1 mol of benzyl bromide in 50 cc. of absolute ethanol. The precipitate formed thereby, which was identified to be the hydrobromide of 5,6-dihydro-6-benzyl-l1H-pyridol[2,3-b] [1,5] benzodiazepine, was separated and dissolved in ethanolic sodium hydroxide. Water was added to the resulting solution, whereby a precipitate was formed which was separated, dried and recrystallized from cyclohexane. The product had a melting point of 111-112" C. It was identical with the end product of Example 3(b). The yield was 75% of theory.

EXAMPLE 8 Preparation of 5,6-dihydr0-5-awo-6('y-dimefhylamino-m propyl) -11H-pyrid0-[2,3-b] [1,5] benzoiazepine and 5,6- dihydr0-6-*('y-dimethylamino-n-propyl) -11H 7 pyrido [2, 34)] [1,5] benzodiazepine by method A (a) 0.2 mol of 'y-dimethylarnino-n-propyl chloride was added to a suspension of 0.1 mol of the 6-sodium derivative of 5,6-dihydro-5-oxo-llH-pyrido[2,3-b][1.5]benzodiazepine (obtained pursuant to Example 3(a) and the mixture was refluxed for four hours while stirring. Thereafter, the reaction mixture was filtered, the filtrate was evaporated in vacuo, and the oily residue was distilled. The fraction passing over between and 200 C. at 0.05 mm. Hg crystallized upon cooling. Recrystallized from gasoline, it had a melting point of 101-102 C. It was identified to be 5,6-dihydro-5-oxo-6-(y-dimethylamino-n-propyl) -1 lH-pyrido [2,3 b] 1,5 benzodiazepine of the formula The yield was 63% of theory.

AnaZysis.C H N O; mol. wt. 296.4. Calculated: C, 68.89%; H, 6.80%; N, 18.91%. Found: C, 69.01%; H, 6.94%; N, 19.06%.

Its hydrochloride had a melting point of 219-220 C. (recrystallized from ethanol).

Analysis.C H ClN O; mol. wt. 332.8. Calculated: C, 61.34%; H, 6.3 6%; Cl, 10.65%; N, 16.84%. Found: C, 61.10%; H, 6.47%; Cl, 10.87%; N, 16.60%.

(b) The free base product obtained in step (a) was reduced with lithium aluminum hydride and the reaction mixture was worked up, as described in Example 1(b).

9 The reduction product had a melting point of 87-88 C. (recrystallized from cyclohexane). It was identified to be 5,6 dihydro 6 ('y dimethylamino n propyl) 11H- pyrido[2,3-b] [1,5]benzodiazepine of the formula CHFCHQ CHE N(OHS)Q Analysis.-C H N mol. wt. 282.4. Calculated: C, 72.31; H, 7.85%; N, 19.84%. Found: C, 72.30%; H, 7,72%; N, 19.83%.

EXAMPLE9 Preparation of ,6-dihydr0-5 -ox0-6,8,9-trimethy l-] 1 H -pyr id0[2,3-b] [1,5]benzodiazepine and 5,6-dihydro-6,8,9- trimethyl 11H pyrido[2,3-b [1,5]benz0diazepine by method A (a) Using a procedure analogous to that described in Example 1(a), 5,6-dihydro-5-oxo-6,8,9-trimethyl-1lH-pyrido[2,3-b] [1,5]benzodiazepine, M.P. 202-294 C. (recrystallized from ethanol), of the formula was prepared from 5,6-dihydro-5-oxo-8,9-dimethy1-11H- pyrido[2,3-b [1,5]benzodiazepine and methyliodide. The yield was 75% of theory.

Analysis.C H N O; mol. wt. 253.3. Calculated: C, 71.13%; H, 5.97%; N, 16.59%. Found: C, 71.20%; H, 6.14%; -N, 16.69%.

(b) The product obtained in step (a) was reduced with lithium aluminum hydride and the reaction mixture was worked up, as described in Example 1(-b), yielding 5,6 dihydro 6,8,9 trimethyl 11H pyrido[2,3-b] [1,5]benzodiazepine, M.P. 152-154" C. (recrystallized from ethanol), of the formula r GHQ-N \N CH3 Analysis.C H N mol wt. 239.3. Calculated: C, 75.28%; H, 7.16%; N, 17.51%. Found: C, 75.60%; H, 7.21%; N, 17.60%.

EXAMPLE 10 Preparation of 5,6 dihydro 5 0x0-6-(,d-a'imethylwmino ethyl) 8,9 dimethyl 11H pyrido[2,3-b] [1,5]ben;- zodiazepine and 5,6-dihydro-6-(B-a'imethylamino-ethyl) 8,9 dimethyl-I1H-pyrial0 [2,3 b] [1,51benz0diazepine by method A (a) Using a procedure analogous to that described in Example 2(a), 5,6-dihydro-5-oxo-6-ethyl-8,9 dimethyl- 11H pyrido[2,3 b][1,5]benzodiazepine was prepared from 5,6-dihydro-5-oxo-8,9-dirnethyl-11H-pyrido[2,3-b] [1,5]benzodiazepine and ethyliodide. The product had a melting point of 162-163 C. (recrystallized from ethanol).

AllalySiS-C H17N3O; mol. wt. 267.3. Calculated: C, 71.89%; H, 6.41%; N, 15.72%. Found: C, 71.60% H, 6.56%; N, 15.58%.

(b) The product obtained in step (a) was reduced with lithium aluminum hydride and the reaction mixture was worked up, as described in Example 1(b). The reduction product had a boiling point of 145-147 C. at 0.03 Hg.

It was identified to be 5,6-dihydro-6-ethyl-8,'9 dimethyl- 11H-pyrido[2, 3-b] [1,5 ]'benzodiazepine.

Analysis.C H N mol. wt. 253.3. Calculated: C, 75.85%; H, 7.56%; N, 16.59%. Found: C, 75.60%; H, 7.65%; N, 16.86%.

EXAMPLE 12 (a) Using a procedure analogous to that described in Example 2(a), 5,6 dihydro-5-oxo-6-ethyl-81(or 9)-chl0ro- 11H pyrido[2,3 b] [1,5]benzodiazepine was prepared from 5,6-dihydro-5-oxo-8(or 9)-chl0r0-11H-pyrido[2,3- b] [1,5]benzodiazepine and ethyliodide. Recrystallized from isopropanol, the product had a melting point of 179181 C.

Analysis.C H ClN O; mol. wt. 273.7. Calculated: C, 61.43%; H, 4.42%; N, 15.35%. Found: C, 61.45%; H, 4.25%; N, 15.25%.

(b) The product obtained in step (a) was reduced with lithium aluminum hydride and the reaction mixture was worked up, as described in Example 1(b). The reduction product had a melting point of 125127 C. (recrystallized from ethanol). It was believed to be 5,6-dihydro-6- ethyl-8 (or 9) -chloro-1 1H-pyrido[2,3-b] [1,5 ]benzodiazepine.

Analysis.C H ClN mol. wt. 25 9.7. Calculated: C, 64.74%; H, 5.43%; N, 16.18%; Cl, 13.65%. Found: C, 64.80%; H, 5.50%; N, 16.18%; Cl. 13.40%.

EXAMPLE 13 (a) Using a procedure analogous to that described in Example 5(a), 5,6-dihydro-5oxo-6- (B-dimethylaminoethyl 8(or 9) methyl 11H pyrido[2,3 b][1,5] benzodiazepine was prepared from 5,6-dihydro-5-oxo-8 (or 9) -methyl-1 1H-pyrid0[2,3-b] [1,5]benzodiazepine and fi-dimethylamino-ethyl chloride. Recrystallized from gasoline, the product had a melting point of C.

Analysis.C H N O; mol. wt. 296.4. Calculated: C, 68.89%; H, 6.80%; N, 18.91%. Found: C, 69.00%; H, 6.91%; N, 19.04%.

(-b) The product obtained in step (a) was reduced with lithium aluminum hydride and the reaction mixture was worked up, as described in Example 1(b). The reduction product had a boiling point of 157l59 C. at 0.02 mm. Hg. It was believed to be 5,6-dihydro-6-(fi-dimethylaminoethyl)-8 (or 9) methyl 11H pyrido[2,3-b] [1,5]benzodiazepine.

Analysis.C H N.,: mol. wt. 296.4. Calculated: C,

11 72.93%; H; 8.16%; N, 18.91%. Found: C, 72.90%; H, 8.29%; N, 19.19%.

EXAMPLE 14 (a) Using a procedure analogous to that described in Example (a), 5,6-dihydro-5-oxo-6-(fi-morpholino-ethyl)- l1H-pyrido[2,3-b] [1,5]be11zodiazepine, M.P. 161-16 2 C. (recrystallized from isopropanol), of the formula Analysis.C H N O; mol. wt. 31014. Calculated: C, 69.65%; H, 6.98%; N, 18.05%. Found: C, 69.75%; H, 7.33%; N, 18.36%.

EXAMPLE 15 (a) Using a procedure analogous to that described in Example 5(a), 5,6 dihydro 5 oxo 6 (B morpholino ethyl) 8,9 dimethyl 11H pyrido[2,3 b] 1,5]

.benzodiazepine, M.P. 14-9l50 C. (recrystallized from ethanol), was prepared from 5,6-dihydro-5-oxo-8,9-dimethyl-1 1H-pyrido[2,3b] [1,51benzodiazepine and ,8-

.rnorpholinoethyl chloride.

Analysis. C H N O mol. wt. 352.4. Calculated:

c, 68.16%;11, 6.86%; N, 15.90%. Found: 0, 68.35%;

(b) The product obtained in step (a) was reduced with lithium'aluminum hydride and the reaction mixture was Worked up, as described in Example 1(b). The reduction product had a boiling point of l93-196 C. at 0.02 mm. Hg and was identified to be 5,6-dihydro-6-(B- morpholino-ethyl) 8,9-dimethyl-llH-pyrido[2,3-b] [1,5] benzodiazepine.

Analysis.-C H O mol. wt. 338.5. Calculated: C, 70.97%; H, 7.74%; N, 16.55%. Found: C, 70.65%; H, 7.86%; N, 16.70%.

EXAMPLE 16 Using a procedure analogous to that described in Example 2 (a), 5,6-dihydr0-5-oxo-6-isobutyl-11H-pyrido[2,

3-b] [1,5]benzodiazepine, M.P. 125127 C. (recrystallized from cyclohexane), of the formula 0 CHr-CEHCHs):

1?. was prepared from 5,6-dihydro-5-oxo-11H-pyrido[2,3-b] [l,5]benzodiazepine and isobutyliodide.

Analysis.-C H N O; mol. wt. 267.3. Calculated: C, 71.91%; H, 6.41%; N, 15.72%. Found: C, 71.90%; H, 6.41%; N, 15.90%.

EXAMPLE 17 Using a procedure analogous to that described in ample 2(a), 5,6-dihydro-5-oxo-6-allyl-1lH-pyrido[2,3-b] [1,51benzodia2epine, M.P. 107 C. (recrystallized from ethanol), of the formula CHa-CH CHz was prepared from 5,6-dihydro-5-ozo-11H-pyrido[2,3-b] [1,5 benzodiazepine and allylbromide.

Analysis.-C H IJ 0; mol. wt. 251.3. Calculated: C, 71.69%; H, 5.21%; N, 16.73%. Found: C, 71.80%; H, 5.50%; N, 16.82%.

EXAMPLE 18 Using a procedure analogous to that described in Example 2(a), 5,6-dihydro-5-oxo-6-(fl-methoxy ethyl)- 111-1 pyrido[2,3 b] [1,51benzodiazepi-ne, M.P. 126 C. (recrystallized from a mixture of ethanol and water), of the formula was prepared from 5,6-dihydro-5-oxo-11H-pyrido[2,3-b] [1,5]benzodiazepine and fi-methoxyethyl chloride.

Analysis.C H N O mol. wt. 269.3. Calculated: C, 66.90%; H, 5.61%; N, 15.61%. Found: C, 67.20%; H, 5.85%; N, 15.85%.

EXAMPLE 19 Using a procedure analogous to that described in Example 2(a), 5,6-dihydro-5-oxo-6-('y-chloro-n-propyl-l1H- pyrid0[2,3-b] [1,5]benzodiazepine, M.P. 128-130 C. (recrystallized from ethanol), of the formula was prepared from 5,6-dihydro-5-oxo-l1H-pyrido[2,3-b] [l,5]benzodiazepine and -chloro-n-propyl iodide.

Analysis.C H ClN O; mol. wt 287.7. Calculated: C, 62.61%; H, 4.90%; N, 14.61%; C1, 12.32%. Found: C, 62.90%; H, 5.05%; N, 14.60%; Cl, 12.00%.

EXAMPLE 20 Using a procedure analogous to that described in Example 2(a), 5,6-dihydro-5-oxo-6- (p-chl0ro-benzyl)l1H 13 pyrido[2,3-b] [1,5]benzodiazepine, M.P. 205207 C. (recrystallized from ethanol), of the formula II I CN U N l was prepared from 5,6-dihydro-5-oXo-1lHpyrido[2,3-b] [1,5]benzodi-azcpine and p-chlorobenzyl chloride.

Analysis.-C H ClN O; mol. Wt. 335.8. Calculated: C, 67.96%; H, 4.20%; N, 12.52%; Cl, 10.56%. Found: C, 67.80%; H, 4.28%; N, 12.37%; Cl, 10.77%.

EXAMPLE 21 Using a procedure analogous to that described in Example 2(a) 5,6-dihydro-5-oXo-6-( -[N-methyl-piperazino1-n-propyl) 11H-pyrido[2,3-b] [1,5]benzodiazepine, M.P. 132l33 C. (recrystallized from cyclohexane), of the formula at L/ S o was prepared from 5,6-dihydro-5-oxo-11H-pyrido[2,3-b] [1,5]benzodiazepine and 'y (N' methyl piperaZino)-npropyl chloride.

Analysis.C H N O; mol. wt. 351.5. Calculated: C, 68.34%; H, 7.17%; N, 19.92%. Found: C, 68.55%; H, 7.25%; N, 20.05%.

EXAMPLE 22 Using a procedure analogous to that described in EX- ample 2(a), the compound believed to be 5,6-dihydro- 5-oxo-6-('y-dirnethylamino-n-propyl) -8 (or 9)-chloro-11H- pyrido[2,3-b][1,5]benzodiazepine, B.P. 212 C., was prepared from 5,6 dihydro--oxo-8(or 9)-chloro 11H- pyrido[2,3-b][1,5]benzodiazepine and 'y-dimethylaminon-propyl chloride.

Analysis.C H ClN O; mol. wt. 330.8. Calculated: C, 61.72%; H,5.79%; N, 16.93%. Found: C, 61.40%; H, 5.87%; N, 16.82%.

EXAMPLE 23 Using a procedure analogous to that described in Example 2(a), the compound believed to be 5,6-dihydro-5- ro-11'H pyrido[2,3-b] [1,5]benzodiazepine, M.P. 164- 166 C. (recrystallized from ethylacetate), was prepared from 5 ,6-dihydro-5 -oxo-8 (or 9)-chloro-11H-pyrido[2,3- b] ['1,5]benzodiazepine and 'y-(N'-methyl-piperazino)-npropyl chloride.

Analysis.C H ClN O; mol. wt. 385.9. Calculated: C, 62.25%; H, 6.27%; N, 18.15%; Cl, 9.19%. Found: C, 62.00%; H, 6.30%; N, 18.45%; Cl, 9.38%.

EXAMPLE 24 Using a procedure analogous to that described in Example 2(a), 5,6 dihydro-5-oxo-6-(*y-dimethylamino-npropyl)-8,9-dimethyl 11H pyrido[2,3-b] [1,5]benzodiazepine, M.P. 143145 C. (recrystallized from cyclohexane), was prepared from 5,6-dihydro-5-oxo-8,9-dimethyl 11H-pyrido[2,3-b] [1,5]benzodiazepine and 'y-dimethylamino-n-propyl chloride.

Analysis.-C C N O; mol. wt. 324.4. Calculated: C, 70.34%; H, 7.46%; N, 17.27%. Found: C, 70.20%; H, 7.48%; N, 17.38%.

14 EXAMPLE 25 Using a procedure analogous to that described in Example 2'(a), 5,6-dihydro-5-oXo-6-(fi-piperidino-ethyl)-8,9- dimethyl 11H pyrido[2,3 b] [1,5]benzodiazepine, M.P. 147-148 .C. (recrystallized from cyclohexane), of the was prepared from 5,6-dihydro-5-oxo-8,9-dimethyl-11H- pyrido[2,3-b][1,5]benzodiazepine and fi-piperidino-ethyl chloride.

Analysis.C H N O; mol. wt. 350.5. Calculated: C, 71.97%; H, 7.48%; N, 15.98%. Found: C, 71.90%; H, 7.54%; N, 15.50%.

EXAMPLE 26 Using a procedure analogous to that described in EX- ample 2(a), 5,6 dihydro-5-oxo-6-( -[N'-methylpiperazinoJ-n-propyl) 8,9 dimethyl-l1H-pyrido[2,3-b][1,5] benzodiazepine, M.P. 129-131" C. (recrystallized from cyclohexane), was prepared from 5,6-dihydro-5-oXo-8,9- dimethyl-l1H-pyrido[2,3-b] [1,5]benzodiazepine and 'y- (N-methylpiperazino) -n-propyl chloride.

Analysis.C H N O; mol. Wt. 379.5. Calculated: C, 69.62%; H, 7.70%; N, 18.46%. Found: C, 69.50%; H, 7.88%; N, 18.40.

EXAMPLE 27 Using a procedure analogous to that described in Example 2(a), the compound believed to be 5,6-dihydro-5 oXo-6-('y-dimethylamino-mpropyl) 8(or 9)-methyl-'11H- pyrido[2,3-b][1,5]'benzodiazepine, B.P. 192-193 C., M.P. 98 C. (recrystallized from petroleum ether), was .prepared from 5,6-dihydro-5-oXo-8-(or 9)methyl- 11H-pyrido[2,3-'b] [1,5]benzodiazepine and 'y-dimethylamino-n-propyl chloride.

Analysis.C H N O; mol. wt. 310.4. Calculated: C, 69.65%; H, 7.15%; N, 18.05%. Found: C, 69.90%; H, 7.31%; N, 17.90%.

EXAMPLE 28 EXAMPLE 29 Using a procedure analogous to that described in EX- ample 2*(a), 5,6 dihydro-5-oXo-6- (p-methoXy-benzyl)- 11H-pyrido[2,3-b][1,5]benzodiazepine, M.P. 193195 C. (recrystallized from ethanol), of the formula was prepared from 5,6 dihydro-5-oxo-l1H-pyrido[2,3-b] 1,5 ]benzodi azepine and p-methoxy-benzyl chloride.

15 Anwlysis.C H N O mol. wt. 331.4. Calculated: C, 72.49%; H, 5.17%; N, 12.68%. Found: C, 72.50%; H, 5.20%; N, 12.62%.

EXAMPLE 30 Using a procedure analogous to that described in EX- ample 2(a), the compound believed to be 5,6-dihydro-5- oxo-6- benzyl-8(or 9)rnethyl 11H pyrido[2,3-b] [1,5] benzodiazepine, M.P. 135136 C. (recrystallized from cyclohexane), was prepared from 5,6-dihydro-5-oXo-8(or 9)-methyl 11H pyrido[2,3-b] [1,5]benzodiazepine and benzyl bromide.

Analysis.C H -;N O; mol. wt. 315.4. Calculated: C, 76.17%; H, 5.43%; N, 13.33%. Found: C, 76.35%; H, 5.59%; N, 13.43%.

EXAMPLE 3 1 Using a procedure analogous to that described in EX- ample 2(a), the compound believed to be 5,6-dihydro-5- oxo-6-(p-ch1orobenzyl) -8(or 9) -methyl-11H-pyrido [2,3-

g b] [1,51benzodiazepine, M.P. 174176 C. (recrystallized from ethanol), was prepared from 5,6-dihydro-5-oxo-8 (or 9)-met-hyl-l1H=pyrido[2,3-b] [1,S]benzodiazepine and pchlorobenzyl chloride.

Analysis.C H ClN O; mol. wt. 349.9. Calculated: C, 68.67%; H, 4.61%; N, 12.02%; Cl, 10.13%. Found: C, 68.60%; H, 4.87%; N, 12.45%; Cl, 10.03%.

EXAMPLE 32 Using a procedure analogous to that described in EX- ample 2(a), 5,6 dihydro-5-oXo-6-(fl-piperidino-ethyl)- 11H pyrido[2,3-b] [1,5]benzodiazepine, BP 193- 196 C., was prepared from 5,6-dihydro 5 oxo 11H- pyrido[2,3-b][l,5]benzodiazepine and B-piperidino-ethyl chloride.

Anialysis.C H N O; mol. wt. 322.4. Calculated: C, 70.86%; H, 6.89%; N, 17.40%. Found: C, 70.90%; H, 6.91%; N, 17.66%.

EXAMPLE 33 Using a procedure analogous to that described in Example 2(a), the compound believed to be 5,6-dihydro-5- oxo-6-methyl-8(or 9)-chloro 11H pyrido[2,3-b] [1,5] benzodiazepine, M.P. 184486 C. (recrystallized from ethanol), was prepared from 5,6-dihydro-5-oxo-8(or 9)- chloro-11H-pyrido[2,3-b][1,5]benzodiazepine and methyl iodide.

Analysis.C H ClN O; mol. wt. 259.7. Calculated: C, 60.12%; H, 3.88%; N, 16.19%; Cl, 13.65%. Found: C, 60.35%; H, 4.01%; N, 16.17%; C1, 13.58%.

7 EXAMPLE 34 Using a procedure analogous to that described in EX- ample 2(a), the compound believed to be 5,6-dihydro-5- 0xo-6-ethyl-8(or 9)-methyl 11H-pyrido[2,3-b] [1,5]benzodiazepine, M.P. 119122 C. (recrystallized from acetonitrile), was prepared from 5,6-dihydro-5-oXo-8(0r 9)- methyl-11H-pyrido[2,3-b] [1,5]benzodiazepine and ethyl iodide.

Analysis.C H N O; mol. wt. 253.3. Calculated: C, 71.13%; H, 5.97%; N, 16.59%. Found: C, 71.10%; H, 5.99%; N, 16.78%.

EXAMPLE 35 Using a procedure analogous to that described in Example 2(a), the compound believed to be 5,6-dihydro-5- oxo-6-allyl-8(or 9)-methyl-11H-pyrido[2,3-b] [1,5]benzodiazepine, M.P. 133-135" C. (recrystallized from petroleum ether), was prepared from 5,6-dihydro-5-oxo-8(or 9)-methyl 11H pyrido[2,3-b][1,5]benzodiazepine and allyl bromide.

Analysis.C H N O; mol. wt. 265.3. Calculated: C, 72.43%; H, 5.70%; N, 15.84%. Found: C, 72.40%; H, 5.72%; N, 15.55%.

1 5 EXAMPLE 36 Using a procedure analogous to that described in Example 2(a), 5,6-dihydro-5-oXo-6-allyl-8,9-dimethyl-l1H- pyrido[2,3-b] [1,51benzodiazepine, M.P. 148149 C. (recrystallized from ethanol), was prepared from 5,6-dihydro-5-oXo-8,9-dimethyl-11H pyrido[2,3-b] [1,51benzodiazepine and allyl bromide.

Analysis.C H N O; mol. Wt. 279.3. Calculated: C, 73.09%; H, 6.13%; N, 15.06%. Found: C, 72.80%; H, 6.08%; N, 15.02%.

EXAMPLE 37 Using a procedure analogous to that described in Example 2(a), the compound believed to be 5,6-dihydro-5- 0X0 6(fi-piperidino-ethyl)-8(or 9)-chloro-11H-pyrido[2, 3-b] [1,51benzodiazepine, M.P. 171 C. (recrystallized from ethanol), was prepared from 5,6-dihydro-5- OX0 8(or 9)-chloro-11H-pyrido[2,3-b][1,5]benz0diazepine and ,B-piperidino-ethyl chloride.

An:alysz's.C H ClN O; mol. wt. 356.8. Calculated: C, 63.95%; H, 5.93%; N, 15.70%; Cl, 9.94%. Found: C, 63.65%; H, 5.99%; N, 15.82%; Cl, 10.08%.

EXAMPLE 39 Using a procedure analogous to that described in Example 2(a), the compound believed to be 5,6-dihydro-5- oxo-6-(B-piperidino-ethyl) -8 (or 9 -methyl-1 1H-pyrido[2, 3-b] [1,5]benzodiazepine, M.P. 156-157 C. (recrystallized from isopropanol), was prepared from 5,6-dihydro- 5-oXo-8(or 9 -rnethyl-1 1H-pyrido[2,3-b] [1,5 benzodiazepine and fl-piperidino-ethyl chloride.

Analysis.C H N O; mol. wt. 336.4. Calculated: C, 71.42%; H, 7.18%; N, 16.65%. Found: C, 71.20%; H, 7.28%; N, 16.90%.

EXAMPLE 40 Using a procedure analogous to that described in Example 2(a), 5,6-dihydro-5-oxo-6-(2'-methyl-allyl)-8,9-dimethyl-11H-pyrido[2,3-b] [1,5]benzodiazepine, M.P. 197- 200 C. (recrystallized from ethanol), of the formula was prepared from 5,6-dihydro-5-oXo-8,9-dimethyl-11H- pyrido[2,3-b] [1,5]benzodiazepine and Z-methylallyl chloride.

Analysis.--C H N O; mol Wt. 293.4. Calculated: C, 73.70%; H, 6.52%; N, 14.33%. Found: C, 74.00%; H, 6.83%; N, 14.05%.

EXAMPLE 41 Using a procedure analogous to that described in Exmple (a), the compound believed to be 5,6-dihydro-5- oxo-6-allyl-8(or 9) -chloro-1 lH-pyrido [2,3-b] [1,5 ]benzodiazepine, M.P. 167-169 C. (recrystallized from ethan01), Was prepared from S,6-dihydro-5-oxo-8(or 9)- 17 chloro 11H-pyrido [2,3-b] [1,5 Jbenzddiazepine and allyl bromide.

Analysis.C H ClN O; mol. wt. 285.7. Calculated: C, 63.05%; H, 4.23%; N, 14.71%; Cl, 12.41%. Found: C, 63.10%; H, 4.15%; N, 14.67%; Cl, 12.35%.

EXAMPLE 42 Using a procedure analogous to that described in Example 1(b), 5,6 dihydro-6-(/3-piperidino-ethyl)-8,9-dimethyl 11H-pyrido[2,3-b][1,5]benzodiazepine, B.P. 187-l90 C., of the formula was prepared by reducing 5,6-dihydro-5-oxo-6-(,B-piperidinoethyl) 8,9 dimethyl-llH-pyrido[2,3-b] [1,5 Jbenzodiazepine with lithium aluminum hydride.

Analysis.C- H N mol. Wt. 336.5. Calculated: C, 74,96.%; H, 8.39%; N, 16.65%. Found: C, 74.50%; H, 8.48%; N, 16.85%.

EXAMPLE 43 Using a procedure analogous to that described in EX- ample 1('b), the compound believed to be 5,6-dihydro-6- ('y [N methylpiperazino]-n-propyl)-8(or 9) chloro- 11H-pyrido[2,3-b][1,5]benzodiazepine, B.P. 210- 212 C., was prepared by reducing 5,6-dihydro-5-oxo-6- ('y [N' methylpiperazino]-n-propyl)-8(or 9) chloro- 11H-pyrido[2,3-b][1,5]benzodiazepine with lithium aluminum hydride.

Analysis.-C H N mol. wt. 310.4. Calculated: C, 64.59%; H, 7.05%; N, 18.83%; Cl, 9.53%. Found: C, 64.50%; H, 7.25%; N, 19.10%; Cl, 9.70%.

EXAMPLE 44 Using a procedure analogous to that described in Example 1(b), the compound believed to be 5,6-dihydro-6- ('y-[N'-methy1piperazino] n propyl)-8(or 9)-methyl- 11H-pyrido[2,3-b][1,5-benzodiazepine, B.P. '197 C., was prepared by reducing 5,6-dihydro-5-oxo-6-( -[N'- methylpiperazino] -n-propyl) -8 (or 9) -methyl-1 lH-pyn'do [2,3-b][1,5]benzodiazepine with lithium aluminum hydride.

Analysis.C H N mol; wt. 351.5 Calculated: C, 71.76%; H, 8.31%; N, 19.93%. Found: C, 71.85%; H,

EXAMPLE 45 Using a procedure analogous to that described in Example 1(b), 5,6-dihydro-6-(y-dimethylamino-npropyl) 8,9 dimethyl 11H pyrido[2,3-b] [1,5]benzodiazepine, B.P. 196-197 C., was prepared by reducing 5,6-dihydro-5-oXo-6-('y-dimethylamino n propyl)-8,9-dimethyl 11H-pyrido[2,3-b][1,5]benzodiazepine with lithium aluminum hydride.

Anrzlysis.-C H N mol. Wt. 310.4. Calculated: C, 73.51%; H, 8.44%; N, 18.05%. Found: C, 73.50%; H,

EXAMPLE 46 Using a procedure analogous to that described in EX- ample 1 b 5 ,6-dihydro-6- ('y- [N'-methylpiperazino] -npropyl) 8,-9-dimethyl-11H pyrido [2,3-b] [1,5]benzodiazepine, B.P. 2'03-206 C., was prepared by reducing pyl) 8,9 dimethyl-l1H-pyrido[2,3-b][1,51benzodiazepine with lithium aluminum hydride. 9

Analysis.C H N mol. Wt.'365.5. Calculated: C, 72.29%; H, 8.55%; N, 19.16%. Found: C, 72.20%; H, 8.85%; N, 19.25%.

EXAMPLE 48 Using a procedure analogous to that described in EX- ample 1(b), the compound believed to be 5,6-dihydro- 6 ethyl 8(or 9)-methyl-11H-pyrido[2,3-b] [1,5]benzodiazepine, B.P. 136 C., was prepared by reducing 5,6 dihydro 5-oxo-6-ethy1-8(or 9)-methyl-11Hpyrido [2,3-b][1,5]benzodiazepine with lithium aluminum hydride.

Analysis.-C H N mol. wt. 239.7. Calculated: C, 75.28%; H, 7.16%; N, 17.56%. Found C, 75.05%; H, 7.20%; N, 17.80%.

EXAMPLE 49 Using a procedure analogous to that described in Example 1('b), the compound believed to be 5,6-dihydro- 6-benzyl-8(or 9) methyl-11H-pyrido[2,3-b][1,5]benzodiazepine, M.P. 138-140 C. (recrystallized from cyclohexane), was prepared by reducing 5,6-dihydro-5-oxo-6- benzyl 8(or 9)-methyl-11H-pyrido[2,3-b][1,5]'benzodiazepine with lithium aluminum hydride.

Analysis.-C H N mol. wt. 301.4. Calculated: C, 79.70%; H, 6.35%; N, 13.95%. Found: C, 79.70%; H, 6.43%; N, 13.65%.

EXAMPLE 50 Using a procedure analogous to that described in Example 1(b), the compound believed to be 5,6-dihydro- ,6 (p-chloro-benzyl)-8(or 9)-methyl-11H-pyrido[2,3-b] [1,5]benzodiazepine, M.P. -121 C. (recrystallized from ethanol) was prepared by reducing 5,6-dihydro-5- 0x0 6 (p chloro-benzyl) -8(or 9)-methyl-11H-pyrido [2,3-b][1,5]benzodiazepine with lithium aluminum hydride.

Analysis.C H ClN mol. wt. 335.8. Calculated: C,

71.53%; H, 5.40%; N, 12.51%; Cl, 10.56%. Found: C,

71.60%; H, 5.52%; N, 12.55%; Cl, 10.43%.

EXAMPLE 51 Using a procedure analogous to that described in Example 1(b), the compound believed to be 5,6-dihydro 6-(fi-morph0lin0-ethyD-8 (or 9) methyl 11H pyrido [2,3-b][1,5-]benzodiazepine, B.P. ZOO-202 C., was prepared by reducing 5,6-dihydro-5-oxo-6-(fl-morpholino ethyl)-8(or 9) -methyl-1 1H pyrido [2,3-b] [1,5]be nzodiazepine with lithium aluminum hydride.

Analysis.C H N O; mol. wt. 324.4. Calculated: C, 70.34%; H, 7.46%; N, 17.27%. Found: C, 70.10%; H, 7.74%; N, 17.64%.

EXAMPLE 52 Using a procedure analogous to that described in Example 1(b), the compound believed to be 5,6-dihydro-6-(B- 'piperidino-ethyl) 8 (or 9) methyl-11H-pyrido[2,3-b] [1, 5]benzodiazepine, BR 194-195 C., was prepared by reducing 5,6-dihydro-5-oxo-6 (B-piperidino-ethyl) -8 (or 9 methyl-11H-pyrido[2,3-b] [1,5]benzodiazepine with lithium aluminum hydride.

Analysis.C H N mol. wt. 322.5. Calculated: C,

74.50%; H, 8.13%; N, 17.37%. Found: C, 74.10%; H,

1 9 EXAMPLE 53 Using a procedure analogous to that described in Example 1(b), the compound believed to be 5,6-dihydro-6- j8-dimethylamino-ethyl -8 (or 9) -methyl-1 1H-pyrido[2,3- b] [1,5]benzodiazepine, B.P. 167170 C., was prepared by reducing 5,6-dihydro--oxo-6-(B-dimethylamino-ethyl)-8(or 9)-methyl 11H pyrido[2,3 b] [1,5] benzodiazepine with lithium aluminum hydride.

Anwlysis.C H N mol. wt. 282.4. Calculated: C, 72.30%; H, 7.85%; N, 19.85%. Found: C, 72.15%; H, 7.66%; N, 19.82%.

EMMPLE 54 Using a procedure analogous to that described in Example 1(b), the compound believed to be 5,6-dihydro-6- ('y-dimethylamino-n-propyl) -8 (or 9 -chloro-1 lH-pyrido- [2,3-b] [1,51benzodiazepine, B.P. 174-176 C., was prepared by reducing 5,6-dihydro-5-oxo-6-(' -dimethylamino-n-propyl) -8 (or 9 -chloro-1 lH-pyrido[2,3-b] [1,5] benzodiazepine with lithium aluminum hydride.

Analysis.C H ClN mol. wt. 316.8. Calculated: C, 64.44%; H, 6.68%; N, 17.69%; Cl, 11.19%. Found: C, 64.20%; H, 6.62%; N, 17.85%; Cl 11.08%.

EXAMPLE 5 5 EXAMPLE 56 Using a procedure analogous to that described in Example 7 (b) 5,6-dihydro-6-(B-piperidino-ethyl)-1lH-pyrido- [2,3-b][1,5]benzodiazepine, B.P. 174 C., was prepared from 5,6-dihydro-11H-pyrido[2,3-b][1,51benzodiazepine and ,B-piperidino-ethyl chloride.

Analysis.-C H N mol. wt. 308.5. Calculated: C, 73.99%; H, 7.84%; N, 18.17%. Found: C, 73.70%; H, 7.96%; N, 18.30%.

EXAMPLE 57 Using a procedure analogous to that described in Example 7(b), 5 ,6-dihydro-6-('y[N'-methylpiperazino]-n-propyl) 11H pyrido[2,3-b] [1,51benzodiazepine, B.P. 185190 C., was prepared from 5,6-dihydro-1lH-pyrido- [2,3-b] [1,5]benzodiazepine and v-(N'-methylpiperazino)- n-propyl chloride.

Analysis.-C H N mol. wt. 337.5. Calculated: C, 71.18%; H, 8.06%; N, 20.76%. Found: C, 70.65%; H, 8.17% N, 20.95%.

EXAMPLE 5 8 Using a procedure analogous to that described in Example 7(b), 5,6 dihydro-6-allyl-1lH-pyrido[2,3-b][1,5] benz-odiazepine was prepared from 5,6-dihydro-11H- pyrid0[2,3-b][1,5]benzodiazepine and allyl bromide. Its hydrobromide, prepared by recrystallizing the free base from an ethanolic solution of hydrogen bromide, had a melting point of 184-185 C.

Analysis.C H BrN mol. wt. 318.2. Calculated: C, 56.62%; H, 5.07%; N, 13.20%; Br, 25.11%. Found: C, 56.70% H, 5.15% N, 13.12% Br 25.25%.

EXAMPLE 59 Using a procedure analogous to that described in Example 7(b), the compound believed'to be 5,6-dihydro-6-al1yl- 8(or 9)-methyl-11H pyrido[2,3 b] [1,51benzodiazepirie, LB-P4337 ISO-152 C., was prepared from 5,6-dihyd-ro-8(or 2t) 9) -methyl-1 1H-pyrido[2,3 -b] [1,5 benzodiazepine and allyl bromide.

AildlySiS.-C H 7N mol. wt. 251.3. Calculated: C, 76.46%; H, 6.82%; N, 16.72%. Found: C, 76.20%; H, 6.95%;N, 17.00%.

EXAMPLE 60 Using a procedure analogous to that described in Example 7 (b) 5,6-dihydro-6-allyl-8,9-dimethyl-11H-pyrido[2, 3-b] [1,5]benzodiazepine, B.P. 147148 C., was prepared from 5,6-dihydro-8,9-dimethyl-1lH-pyrido[2,3-b] [1,5]benzodiazepine and allyl bromide.

Analysis.C H N mol. wt. 265.4. Calculated: C, 76.94%; H, 7.22%; N, 15.84%. Found: C, 77.10%; H, 7.43%;N, 15.76%.

The compounds according to the present invention, that is, those embraced by Formula I above and their nontoxic, pharmacologically acceptable acid addition salts, have useful pharmacodynamic properties. More particularly, they exhibit antipyretic, analgesic, sedative, and antiphlogistic activities in warm-blooded animals.

For therapeutic purposes, the compounds of the present invention are administered to warm-blooded animals by the oral or parenteral route as active ingredients in customary dosage unit compositions, that is, compositions in dosage unit form consisting essentially of an inert pharmaceutical carrier and one dosage unit of the active ingredient, such as tablets, coated pills, suspensions, solutions, suppositories, gelatin capsules and the like. One dosage unit of the compounds according to the present invention is from 50 to 400 mgm., preferably mgm.

The following examples illustrate a few dosage unit compositions comprising a compound of the present invention as an active ingredient. The parts are parts by weight.

EXAMPLE 61 Tablets.The tablet composition is compounded from the following ingredients:

Parts 5,6-dihydro-5-oxo-6-allyl-11H-pyrido[2,3-b] [1,5]

benzodiazepine 100.0 Secondary calcium phosphate 93.0 Potato starch 50.0 Gelatin 5.0 Magnesium stearate 2.0

Total 250.0

EXAMPLE 62 Coated p ills.The tablets obtained in Example 61 are coated with a thin shell consisting essentially of talcum and sugar, and the coating is polished with beeswax. Each pill weighs about 400 mgm. and also contains 100 mgm. of the active ingredient.

EXAMPLE 63 Supp0sit0ries.The suppository composition is compounded from the following ingredients:

Parts 5,6-dihydro-5-oxo-6-allyl-11H-pyrido[2,3-b] [1,5]

benzodiazepine 100.0

Cocoa butter 1600.0

Total 1700.0

21 Compounding procedure:

The cocoa butter is melted at 45 C., the finely pulverized pyridobenzodiazepine compound is stirred into the molten mass, the mixture is homogenized, cooled to about 35 C., and poured into cooled suppository molds, each holding 1700 mgm. of the composition. Each suppository contains 100 mgm. of the active ingredient.

Dosage unit compositions comprising a compound of the present invention as an active ingredient may also contain one or more other active ingredients, such as a sedative, analgesic and the like, to complement the action of the pyridobenzodiazepine component, as illustrated by the following example:

EXAMPLE 64 Tablets.The tablet composition is compounded from the following ingredients:

Parts 5,6-dihydro--oxo-6-allyl-1lH-pyrido[2,3-b] [1,5

benzodiazepine 100.0 S-ethyI-S-phenyl-barbituric acid 25 .0 Lactose 60.0 Potato starch 25.0 Polyvinylpyrrolidone 6.0 Colloidal silicic acid 2.0 Magnesium stearate v 2.0

Total 220.0

EXAMPLE 65 Coated pills.-The pill core composition is compounded from the following ingredients:

Parts 5 ,6-dihydro-5 -oxo-6-allyl-1 lH-pyrido [2,3 -b] [1,5]

benzodiazepine 100.0

5-ethyl-5-phenyl-barbituric acid 20.0 Codeine phosphate 10.0 Lactose 38.0 Corn starch 40.0 Soluble starch 10.0 Magnesium stearate 2.0

Total 220.0

Compounding procedure:

The pyridobenzodiazepine compound, the barbituric acid compound, the codeine phosphate, the lactose and one-half of the required amount of the corn starch are intimately admixed with each other, the mixture is moistened with an aqueous 20% solution of the soluble starch, and the moist mass is forced through a 1.5 mm.-mesh screen. The granulate thus obtained is dried at 40 C., again passed through the screen, and admixed with the remaining amount of the corn starch as well as with the magnesium stearate. The resulting mixture is pressed into 220 mgm.-pill cores, which are then coated with a thin shell consisting essentially of talcum and sugar, and the finished pills are polished with beeswax. Each coated pill weighs about 350 mgm. and Contains 100 mgm. of the pyridobenzodiazepine compound, 20 mgm. of the barbituric acid compound and 10 mgm. of codeine phosphate.

Although the above dosage unit composition examples illustrate only one of the compounds according to the present invention as an active ingredient, it should be understood that any of the other compounds embraced by Formula I or non-toxic, pharmacologically acceptable acid addition salts thereof may be substituted for the particular pyridobenzodiazepine compound in Examples 61 through 65. Moreover, the amount of the pyridobenzodiazepine compound in these examples may be varied within the dosage unit limits set forth above, as may the amounts and nature of the inert ingredients.

While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that the invention is not limited to these embodiments and that various changes and modifications may be made without departing from the spirit of the invention or the scope of the appended claims.

I claim:

1. A compound selected from the group consisting of 5,6-dihydro-11H-pyrido[2,3-b] [1,5 benzodiazepine derivatives of the formula t Z-N R" N f wherein R is selected from the group consisting of lower alkenyl, benzyl, halobenzyl, lower alkoxy-benzyl and -AB where A is lower alkylene and B is selected from the group consisting of hydrogen, halogen and lower alkoxy R and R" are each selected lfIOIl'l the group consisting of hydrogen, lower alkyl and halogen, and Z is selected from the group consisting of carbonyl and methylene, and their non-toxic, pharmologically acceptable acid addition salts.

2. A compound selected from the group consisting of 5 ,6-dihydro-l lH-pyrido[2,3-b] [1,5] benzodiazepine derivatives of the formula wherein R is selected from the group consisting of allyl, isobutenyl, benzyl, chlorobenzyl, methoxy-benzyl and -A-B where A is .alkylene of l to 4 carbon atoms and B is selected from the group consisting of hydrogen, chlorine and methoxy R and R are each selected from the group consisting of hydrogen, methyl and chlorine, and Z is selected from the group consisting of carbonyl and methylene, and their non-toxic, pharmacologically acceptable acid addition salts.

3. A compound selected from the group consisting of 5 ,6-dihydro-5 -oxo-1 1H-pyrido[2,3-b] 1, 5 benzodiazepine derivatives of the formula 0 l LN wherein R is selected from the group consisting of allyl, isobutenyl, benzyl, chlorobenzyl, methoxy-benzyl and AB where A is alkylene of 1 to 4 carbon atoms and B is selected from .the group consisting of hydrogen, chlorine and methoxy R and R" are each selected from the group consisting of hydrogen, methyl and chlorine, and

and their non-toxic, pharmacologically acceptable acid addition salts.

4. A compound selected from the group consisting of 5 ,6-dihydro-1 1H-pyrido[2,3-b] [1,5 ]benzodiazepine derivatives of the formula 24 Where A is alkylene of 1 to 4 carbon atoms and B is selected from the group consisting of hydrogen, chlorine and methoxy R and R are each selected from the group consisting of hydrogen, methyl and chlorine, and and their non-toxic, pharmacologically acceptable acid addition salts.

5. 5,6 dihydro-5-oxo-6-allyl-11H-pyrido[2,3-b][1-5] benzodiazepine.

6. 5 ,6-dihydro-5 -ox016-me tihyl-1 1H-pyrid0[2, 3-'b] [1,5] benzodiazepine.

7. 5,6 dihydro-5-oxo-6-ethyl-11H-pyrido[2,3-b][1,5] benzodiazepine.

References Cited UNITED STATES PATENTS 3,038,896 6/1962 Habicht et al 260-239 3,150,125 9/1964 Schmutz et a1. 260-239.3

FOREIGN PATENTS 658,624 2/ 1963 Canada.

ALEX MAZEL, Primary Examiner.

ALTON D. ROLLINS, Examiner. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 5,6-DIHYDRO-11H-PYRIDO(2,3-B)(1,5)BENZODIAZEPINE DERIVATIVES OF THE FORMULA 